The organic cation transporter, OCT1 [SLC22A1], expressed in abundance in the liver, mediates the uptake of small molecular weight hydrophilic organic cations including many drugs, nutrients and toxins. Although OCT1 clearly plays a role in the hepatic disposition of xenobiotics, its physiologic role is unknown. Recently, in preliminary studies, we made a striking and unexpected observation. We observed that knocking out Oct1 markedly reduced fatty liver in leptin deficient mice suggesting that OCT1 plays a critical role in triglyceride accumulation in the liver. The overall goals of the studies proposed in this renewal application are to determine the physiologic role of OCT1 and to explore the pharmacologic inhibition of OCT1 as a therapeutic strategy for fatty liver. Our underlying hypothesis is that OCT1 facilitates triglyceride accumulation in the liver. Three aims are proposed. In studies under Aims 1 and 2, we will identify the pathways through which Oct1 acts on triglyceride accumulation using Oct1 knockout mice (Aim 1) and transgenic mice over- expressing human OCT1 in the liver (Aim 2). Two models of fatty liver will be used: leptin deficient mice, ob/ob, which represent a genetic deficiency model and mice fed high fat Western diets, which mimics the disease in U.S. populations. In Aim 3, we will test small molecule inhibitors of human OCT1 as potential therapies for fatty liver. These studies will greatly advance our understanding of OCT1, a critical hepatic transporter involved in the disposition of xenobiotics.